Virtual discovery of melatonin receptor ligands to modulate circadian rhythms

Reed M. Stein, Hye Jin Kang, John D. McCorvy, Grant C. Glatfelter, Anthony J. Jones, Tao Che, Samuel Slocum, Xi-Ping Huang, Olena Savych, Yurii S. Moroz, Benjamin Stauch, Linda C. Johansson, Vadim Cherezov, Terry Kenakin, John J. Irwin, Brian K. Shoichet (), Bryan L. Roth () and Margarita L. Dubocovich ()
Additional contact information
Reed M. Stein: University of California San Francisco
Hye Jin Kang: University of North Carolina at Chapel Hill
John D. McCorvy: University of North Carolina at Chapel Hill
Grant C. Glatfelter: University at Buffalo (SUNY), The State University of New York
Anthony J. Jones: University at Buffalo (SUNY), The State University of New York
Tao Che: University of North Carolina at Chapel Hill
Samuel Slocum: University of North Carolina at Chapel Hill
Xi-Ping Huang: University of North Carolina at Chapel Hill
Olena Savych: Enamine Ltd
Yurii S. Moroz: National Taras Shevchenko University of Kyiv
Benjamin Stauch: University of Southern California
Linda C. Johansson: University of Southern California
Vadim Cherezov: University of Southern California
Terry Kenakin: University of North Carolina at Chapel Hill
John J. Irwin: University of California San Francisco
Brian K. Shoichet: University of California San Francisco
Bryan L. Roth: University of North Carolina at Chapel Hill
Margarita L. Dubocovich: University at Buffalo (SUNY), The State University of New York

Nature, 2020, vol. 579, issue 7800, 609-614

Abstract: Abstract The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light–dark cycle1–4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1–4,7–9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10–12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists—which were topologically unrelated to previously explored chemotypes—that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3–1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.

Date: 2020
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DOI: 10.1038/s41586-020-2027-0

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